1. Field of the Invention
The present invention relates to the preparation of bromobenzaldehydes bearing hydroxy and/or alkoxy substituents, and in particular the compound 5-bromovanillin.
2. Description of the Prior Art
Bromobenzaldehydes bearing hydroxy and/or alkoxy substituents are known to this art as valuable industrial compounds useful as intermediates in various organic syntheses. Thus, 5-bromovanillin (3-bromo-4-hydroxy-5-methoxybenzaldehyde), bromoprotocatechuic aldehyde (3-bromo-4,5-dihydroxybenzaldehyde) and 3-bromo-4,5-dimethoxybenzaldehyde are useful as intermediates in the preparation of 3,4,5-trimethoxybenzaldehyde which is itself an intermediate for the preparation of such pharmaceuticals as trimethoprim 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine. These bromobenzaldehydes are also useful in the preparation of bromophenylalanines having hypotensive activity (cf. French Pat. No. 1,592,518).
The alkoxy and/or hydroxy substituted bromobenzaldehydes are typically prepared by reacting bromine with the corresponding aldehyde.
And a variety of methods are known for brominating aromatic aldehydes. Thus, it has been proposed to carry out the bromination of hydroxy and/or alkoxybenzaldehydes in various reaction media. The solvent employed most generally is glacial acetic acid containing, if appropriate, an alkali metal acetate, such as sodium acetate (cf. Dakin, Am. Chem. Journal, 42, 477-98 (1909); Torrey et al, J. Am. Chem. Soc., 31, 583-585 (1909); O. S. Brady et al, J. Chem. Soc., 107, 1858-62 (1915); E. I. Shriner et al, J. Am. Chem. Soc., 51, 2194 (1929); R. A. McIvor et al, Can. J. of Chem., 32, 298-302 (1953); Henry et al, J. Chem. Soc., 2279-89 (1930); F. Misani et al, J. Org. Chem., 10, 356 (1945); R. Pschorr, Ann., 391, 23-39 (1912); French Pat. No. 1,592,518). Although this process results in excellent yields of bromobenzaldehydes, particularly in the case of vanillin, it suffers from various disadvantages which make it unattractive from an industrial standpoint. In particular, upon completion of the reaction this process gives rise to a solution of hydrobromic acid in acetic acid from which it is difficult, if not impossible in practice, to recover HBr.
It has also been proposed (cf. R. Pschorr, loc. cit.) to replace the glacial acetic acid with chloroform; in this instance it is difficult to separate the bromobenzaldehyde from the hydrobromic acid contained therein by washing with chloroform, which suggests using a third solvent for the washing and thus making the process too complicated to exploit industrially.
In French Pat. No. 72/38,410, published under No. 2,177,693, a process for brominating vanillin has been described, consisting of adding a solution of vanillin in hydrobromic acid, containing 48% by weight of HBr, to bromine.
Lower alcohols, and particularly ethanol, have also been employed as bromination reaction media (cf. F. Tiemann et al, Ber, 7, 615 [1874]). The conjoint formation of irrecoverable methyl bromide or ethyl bromide which may be difficult to justify economically in large-scale production of bromovanillin makes this process unattractive.
In every instance the reaction leads to the formation of one molecule of hydrobromic acid per molecule of bromobenzaldehydes produced in accordance with the following reaction scheme: ##STR1##
It is found that in such a process only one half of the bromine employed is consumed to form bromobenzaldehydes, with the other half forming hydrobromic acid or, depending upon the solvent employed, alkyl bromides. Recovery and/or economical disposition of these by-products reduce the industrial interest of this process, whatever its application.
From this analysis of the state of the art it follows, therefore, that the conjoint formation of HBr resulting from the use of bromine as a brominating agent presents a serious problem in the industrial application of the known processes.